In the United States, non-melanoma skin cancer that includes basal- and squamous-cell carcinoma is the most frequently diagnosed form of cancer and, according to an estimate, more than a million new cases of skin cancers are diagnosed annually in the USA. Therefore, it is warranted to intensify our efforts for the development of novel approaches for prevention and therapy of this cancer type. Chemoprevention by naturally occurring non-toxic compounds is a potential strategy to prevent the occurrence of the disease. Resveratrol (3,5,4'-trihydroxystilbene), a phytoalexin antioxidant found in grapes, red wines, berries and peanuts has been shown to afford cancer chemopreventive effects in chemically-induced murine skin carcinogenesis. The classical chemical carcinogenesis model of skin cancer is regarded to have little, if any, relevance to humans skin cancers because the excessive exposure to solar ultraviolet (UV) radiation is the major cause of human skin cancers. Our preliminary studies have shown that topical application of resveratrol prevents against chemically induced skin carcinogenesis in SENCAR mice. The molecular mechanism(s) of the biological effects imparted by resveratrol is not well understood. Our recent studies (Clinical Cancer Research, accepted for-publication), have demonstrated that resveratrol treatment to human epidermoid carcinoma (A431) cells results in an induction of the cyclinkinase inhibitor WAFl/p21 that inhibits cyclin (D1/D2)-cdk 6, cyclin (D1/D2)-cdk 4, cyclin E-cdk 2 complexes, thereby resulting in a G1-phase arrest of the cell cycle and an apoptotic death of the cells. We have also found that resveratrol treatment causes a modulation in refinoblastoma (pRb)-E2FDP machinery, during G1-phase arrest and apoptosis of A431 cells. The current application is based on these novel observations, and is designed to investigate the chemopreventive potential of resveratrol against UVB-mediated skin carcinogenesis, and the molecular mechanism(s) by which this food-based polyphenolic antioxidant imparts cancer chemopreventive effects. The central hypothesis of the work proposed in this application is that resveratrol will impart chemopreventive effects against photocarcinogenesis via modulating cki-cyclin-cdk network-mediated cell cycle regulation and apoptosis. In this study, we will first establish cancer chemopreventive potential of resveratrol against UVB-mediated damages including skin tumorigenesis in SKH-1 hairless mice. We will then conduct studies to assess the involvement of cki-cyclic-cdk network as a mechanism of chemopreventive effects of resveratrol during for UVB-mediated responses and skin tumorigenesis in SKH-1 hairless mice. Successful completion of this application will define i) the chemopreventive/therapeutic potential of resveratrol against skin cancer, and ii) molecular mechanism(s) of the biological effects of Resveratrol. This may pave the way for the development of novel strategies for prevention and possibly treatment of skin cancer and other epithelial cancers as well.